Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in cellular membrane structure and the subsequent failure of its function after CNS ischemia were monitored by analyzing changes in the plasma membrane marker enzyme (Na(+) + K(+)-ATPase. The levels of two isozymes of (Na(+) + K(+)-ATPase, alpha+ and alpha, which have distinct cellular and anatomical distributions, were studied to determine if differential cellular damage occurs in primary and peri-ischemic injury areas. The efficacy of monosialoganglioside (GM1) treatment was assessed, since this glycosphingolipid has been shown to reduce ischemic injury by protecting cell membrane structure/function. Using a rat model of cortical focal ischemia, levels of both ATPase isozyme activities were assayed in total membrane fractions from primary ischemic tissue (parietal cortex) and three peri-ischemic tissue areas (frontal, occipital, and temporal cortex) at 1, 3, 5, 7, and 14 days after ischemia. No significant loss of either isozyme's activity occurred in any tissue area at 1 day after ischemia. At 5 days, in the primary ischemic area, both isozyme activity levels decreased by 70-75%. The alpha+ enzyme activity loss persisted up to 14 days, while a 17% recovery in alpha activity occurred. In the three peri-ischemic tissue areas, enzyme activity losses ranged from 42%-59% at 3 days after ischemia. A complete restoration of both isozyme activities was seen at 14 days. After three days of GM1 ganglioside treatment there was no loss of total (Na*+) + K(+)-ATPase activity in the three peri-ischemic areas, and a significantly reduced loss in the primary infarct tissue. An autoradiographic analysis of brain coronal sections using 3H-ouabain supports the enzymatic data and GM1 effects. Reductions in 3H-ouabain binding in all cortical layers at 3 days after ischemia were visualized. GM1 treatment significantly reduced these 3H-ouabain binding losses. In summary, time-dependent quantitative changes in activity levels of ATPase isozymes (alpha+ and alpha) reflect the different degree of membrane damage that occurs in primary vs. peri-ischemic tissues (e.g., irreversible vs. reversible membrane damage), and that ischemia affects cell membranes of all neural elements in a largely similar fashion. GM1 ganglioside was found to reduce plasma membrane damage in all CNS cell types.
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PMID:Loss and recovery of activities of alpha+ and alpha isozymes of (Na(+) + K+)-ATPase in cortical focal ischemia: GM1 ganglioside protects plasma membrane structure and function. 132 61

The N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptor, which gates Ca(2+)-permeable ion channels, is known for its role in learning and memory formation, in the induction of long-term potentiation, and also in seizure activity and neurotoxicity. In primary cultures of cerebellar neurons, agonists of NMDA receptors induce a dose-dependent release of [3H]arachidonic acid ([3H]AA), which is potentiated by activation of the glycine-positive modulatory site and inhibited by NMDA receptor antagonists. NMDA receptor-induced [3H]AA release is inhibited by quinacrine and partially depends on the presence of extracellular calcium. The [3H]AA release is not sensitive, however, to pretreatment with pertussis or cholera toxin, which suggests a Ca(2+)-dependent activation of phospholipase A2 not employing G proteins. Pretreatment of cultures with the natural and semisynthetic sphingolipids GT1b and PKS 3, respectively, inhibits NMDA receptor-mediated [3H]AA release. We also demonstrated glutamate-evoked [3H]AA release from rat hippocampal slices, which is NMDA receptor mediated, calcium dependent and sensitive to quinacrine. Arachidonic acid and its metabolites have been shown to play a role as second messengers and to modulate neuronal activity. Moreover, they are thought to act as transsynaptic modulators in the mechanism of NMDA receptor-induced long-term potentiation in the hippocampus. Their role in ischemic brain pathology has also been postulated. Our experiments on cultured cerebellar granule cells, incubated in a Mg(2+)-free medium deprived of glucose and oxygen, demonstrated a time-dependent stimulation of [3H]AA release. This release was inhibited by antagonists of NMDA receptors and by quinacrine. Stimulation of NMDA-sensitive glutamate receptors and the subsequent calcium-mediated activation of phospholipase A2 may play a role in the in vivo release of arachidonic acid during brain ischemia. This hypothesis is supported by the observation that the enhanced level of thromboxane B2 in the gerbil brain after 5 min of global ischemia is reduced by the systemic application of either the NMDA antagonist MK-801 or the ganglioside GM1.
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PMID:NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. 138 78

The effects of transient forebrain ischemia on the extracellular concentration of the excitatory amino acids glutamate and aspartate were studied in the gerbil hippocampus using microdialysis. Bilateral carotid occlusion (8 min) increased glutamate and aspartate concentration in the dialysate by 3- to 8-fold. This increase lasted 20-30 min. When the animals were pretreated with GM1 ganglioside (30 mg/kg/day, i.p., for 3 days), the ischemia induced increase of excitatory amino acids in the dialysate was significantly reduced. The results are in line with the hypothesis that systemic GM1 ganglioside administration may reduce ischemia-induced brain damage.
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PMID:GM1 ganglioside reduces ischemia-induced excitatory amino acid output: a microdialysis study in the gerbil hippocampus. 158 43

Cortical focal ischemia in the rat was induced by middle cerebral artery occlusion (MCAo) together with permanent occlusion of the ipsilateral common carotid artery (CCAo) and a temporary (1 hr) occlusion of the contralateral CCA. By using a defined cortical tissue sampling procedure at 3, 6, 24, 72, 96, and 120 hr after the MCAo + CCAo, patterns of edema and ion (Na+, K+, and Ca++) changes in a primary and three peri-ischemic cortical areas are described. Ionic imbalances and edema formation have distinct patterns, are time dependent, and are different when comparing primary and peri-ischemic areas. Calcium increases to "neurotoxic" levels appear temporally independent of edema formation, reaching magnitudes 20 times greater than basal levels in the primary infarct area. Na+ increases correlate with increases in water, while K+ losses do not appear to be directly related to edema formation of Na+ and Ca++ increases. K+ losses are only significant in the primary infarct area. Rats treated with GM1 ganglioside (10 mg/kg, i.m.) daily showed significant reductions in edema, Na+ and Ca++ increases. These ganglioside effects were evident as early as 24 hr after the ischemic injury. Ca++ increases, which was maximal at 72 hr after the ischemic injury, was reduced by greater than 50% in GM1-treated animals. The mechanism by which GM1 is an effective neuroprotective agent may be evidenced by its effects on Ca++ influx/efflux processes in injury.
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PMID:Temporal changes in edema, Na+, K+, and Ca++ in focal cortical stroke: GM1 ganglioside reduces ischemic injury. 180 Jul 72

Several authors have demonstrated a correlation between short latency somatosensory evoked potentials (short latency SEPs) and cerebral blood flow (CBF). It is also known that ischemia may modify the amplitude of the cortical SEP while its latency is less sensitive to CBF fluctuations. Phychotropic drugs--Oxiracetam, SAMe, Naloxone, L-acetylcarnitine and GM1--affect some parameters of the early components of cortical SEPs, chiefly the amplitude, which makes SEP recording a useful method for monitoring pharmacological activity in acute stroke.
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PMID:Effects of psychotropic drugs on somatosensory evoked potentials in cerebral ischemia. 187 7

The functional consequences of cortical focal ischemia and the effect of monosialoganglioside (GM1) treatment on learning/performance of a spatial reversal task were investigated. Cortical focal ischemia was induced by a permanent occlusion of the left common carotid artery and the ipsilateral middle cerebral artery, with a 1-h clamping of the contralateral carotid artery. Twenty-six rats were randomly assigned to three groups: sham controls, a saline-treated ischemic group, and a GM1 ganglioside-treated ischemic group (10 mg/kg/day: IM). Fifteen days after surgery rats were trained on a spatial reversal task in a two-lever operant chamber where food reward was contingent on lever pressing. Training continued from day 15 to day 21 after surgery. Cortical focal ischemia resulted in learning/performance deficits that were reduced by GM1 ganglioside treatment. The cognitive deficits were characterized by a significantly higher number of nonperseverative errors and number of responses to criterion. There was a significant difference between left and right lever performance in the saline-treated ischemic group, which was absent in shams and GM1-treated ischemic rats. On all measures GM1-treated rats were not different from sham controls.
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PMID:GM1 ganglioside reduces cognitive dysfunction after focal cortical ischemia. 209 71

Complete obstruction of the maternal blood flow to fetal rats at 20 days of gestation for a period of 10 min causes a significant shift of approximately 22% in protein kinase C (PKC) activity from a cytosolic to a membrane-bound form in the fetal brain. This translocation can be entirely reversed without losses in activity by a single intraperitoneal injection into the gravid rat of either a mixture of disialo- and trisialoganglioside [polysialoganglioside (PSG)] or by GM1 (50 mg/kg of body weight) given 3 h before onset of the ischemic episode. Cessation of blood flow for 15 min followed by a reperfusion period of 24 h results in a 47% loss in total PKC activity. This down-regulation can be almost entirely prevented upon intraperitoneal administration of GM1 3 h before, but also during and even 90 min after the onset of ischemia. The PSG mixture is also effective, particularly when given 3 h before the insult. Down-regulation of PKC is accompanied by an increase in a Ca2(+)-phosphatidylserine-independent kinase [protein kinase M (PKM)] activity, which rises from 30 pmol/min/mg of protein in control animals to a maximal value of 83.1 pmol/min/mg of protein after 15 min of ischemia and 6 h of reperfusion. By 24 h, PKM activity is 46.8 pmol/min/mg of protein. Administration of GM1 blocks completely the appearance of PKM, a result suggesting that PKC down-regulation and PKM activity elevation are intimately associated events and that both are regulated by GM1 ganglioside.
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PMID:Gangliosides prevent ischemia-induced down-regulation of protein kinase C in fetal rat brain. 223 Aug 13

We evaluated the effects of treatment with the inner ester derivative of the monosialoganglioside GM1 on cortical electroencephalographic activity and hippocampal CA1 morphology after transitory, near-complete cerebral ischemia in rats. Ischemia was induced by the four-vessel occlusion method, and we studied only the 58 rats that showed flattening of the cortical electroencephalogram for the entire 30 minutes of occlusion. The ganglioside (n = 30) or saline (n = 28) was administered intravenously immediately after release of the carotid clips and then intramuscularly for 21 days of observation. Cortical electroencephalographic activity was monitored throughout the experiment. After 21 days of recirculation we assessed hippocampal CA1 damage by light microscopy. The results indicate that treatment with the ganglioside reduces postischemic secondary damage to the cortical circuitry (as indicated by significantly higher cortical electroencephalographic activity late after reperfusion) and limits neuronal loss in the CA1 region. Our results lend support to the possible therapeutic use of ganglioside in human pathologic conditions associated with cerebrovascular insufficiencies.
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PMID:Protective effects of a monosialoganglioside derivative following transitory forebrain ischemia in rats. 223 55

The aim of our study was to investigate the changes of various biochemical parameters (concentrations of lactate, free arachidonate, cyclo- and lipoxygenase products) in rat brain after ischemia and reperfusion and the effects of pretreatment with the ganglioside derivative GM1-lactone on the same parameters. Ischemia was induced by reversible occlusion of common carotid arteries for 20 min, which included a final 5 min of respiration of 5% oxygen in nitrogen. Reperfusion was obtained by removing the occlusion. Pre-ischemic conditions were obtained on sham-operated animals. Animals were killed by microwave irradiation of their heads. Brain levels of lactate and of free arachidonate were markedly increased after ischemia and returned to normal values at 5 min of reperfusion. Levels of the cyclooxygenase metabolites prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were increased after ischemia, whereas levels of the lipoxygenase metabolite leukotriene C4 (LTC4) did not change. After reperfusion, a very marked increase of the cyclooxygenase products occurred but not of LTC4. Treatment with GM1-lactone prevented the elevation of cyclo- and lipoxygenase metabolites especially during reperfusion, with limited effects on lactate and free arachidonate levels.
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PMID:Accumulation of arachidonic acid cyclo- and lipoxygenase products in rat brain during ischemia and reperfusion: effects of treatment with GM1-lactone. 250 87

An examination was made of the effects of ganglioside GM1 (i.m.) on the losses of membrane fatty acids (palmitic, stearic, oleic, linoleic, and arachidonic), the plasma membrane enzyme Na+, K+-ATPase, and the mitochondrial membrane enzyme Mg2+-ATPase, associated with global ischemia 24 hr after permanent unilateral occlusion of the carotid artery in Mongolian gerbils. While there was a significant loss of fatty acids in saline controls, no loss was detected in membranes from GM1-injected gerbils. Rather, we found an increase in membrane fatty acid content, indicative of altered turnover. A 38% loss of Na+, K+-ATPase and a 36% loss of mitochondrial Mg2+-ATPase observed in membranes from saline controls was reduced in membranes from GM1-injected animals to losses of 15% and 8% respectively. These effects are further described by analyses of enzyme kinetics (apparent Vmax and apparent Km). After 1 week of storage, the activities of both membrane ATPases from saline controls decreased substantially more than from GM1-injected animals, suggesting that the GM1 membranes were better "preserved." Since there was a minimal loss in protein content after 24 hr of ischemia, these results indicate that systemically injected GM1 may protect structure and function of plama membranes during the acute phases of ischemic injury.
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PMID:GM1 ganglioside treatment after global ischemia protects changes in membrane fatty acids and properties of Na+, K+-ATPase and Mg2+-ATPase. 253 6


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